Analysis of Platelets in Solid Tumor Patients: Profound Changes and Unexpected Findings.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4012-4012
Author(s):  
Tina Wiesner ◽  
Stefanie Bugl ◽  
Joerg T Hartmann ◽  
Lothar Kanz ◽  
Hans-Georg Kopp
Keyword(s):  
Cancer Patients ◽  
Platelet Activation ◽  
Solid Tumor ◽  
Immune Escape ◽  
Conflicts Of Interest ◽  
Tumor Patients ◽  
Vascular Walls ◽  
Scavenger Activity ◽  
Thrombospondin 1

Abstract Abstract 4012 Poster Board III-948 Introduction Platelets are important contributors to several hallmarks of tumor pathophysiology including immune escape of disseminated malignant cells, metastasis, and neoangiogenesis. Following activation, platelets release their granule content, which contains a plethora of factors that may both inhibit and stimulate angiogenesis, immunosurveillance, plasmatic coagulation, or tumor growth. Targeted deletion of thrombospondin-1 and -2 from the platelet proteome leads to altered secretion of CXCL12 and matrix metalloproteinases (MMPs) in mice (Kopp HG, Hooper AT et al., J Clin Invest 2006), and platelets derived from 25 patients with lymphoma, colorectal and ovarian cancer displayed a diminished tsp-1/VEGF-ratio (Gonzalez FJ, Rueda A et al., Int J Biol Markers, 2004). We therefore set out to analyze a carefully selected patient cohort for in vivo platelet activation and platelet contents in order to define phenotypic changes in the setting of disseminated malignancy. Patients and methods Platelet activation in percent of P-selectin positive platelets and platelet contents (i.e. absolute platelet count-corrected plasma/serum levels of VEGF-A, CXCL12 [SDF-1], CXCL4 [pf4], and thrombospondin-1) were analyzed. Patients were eligible after written informed consent if they had a first diagnosis of metastatic malignancy, were not taking medication on a regular basis, and had not taken any medication during the last 14 days before venipuncture. Healthy age- and sex-matched subjects were used as controls. Results (mean ± SEM) Tumor patients had increased platelet counts (301,558 ± 17,489/μl vs. 234,111 ± 5,946/μl) and slightly lower hematocrits. In addition, cancer patients displayed significantly elevated percentages of activated platelets as measured by CD62P expression (1.14 ± 0.20% vs. 0.24 ± 0.03%). In order to obtain absolute platelet contents per 100 million platelets, we took tumor-associated thrombocytosis and anemia in consideration and calculated as follows: ([serum VEGF/CXCL12/TSP1/CXCL4 – plasma VEGF/CXCL12/TSP1/CXCL4] * [1-hematocrit] ÷ platelets per ml whole blood) * 100×106. The results showed highly significant changes, including increased contents of VEGF (143.24 ± 15.87 pg vs. 63.02 ± 6.28 pg; p < 0.001) and decreased amounts of thrombospondin-1 (2,925.13 ± 217.78 ng vs. 3,764.34 ± 184.64 ng; p = 0.005), CXCL4 (1,547.60 ± 44.54 ng vs. 1,132.32 ± 55.62 ng, p<0.001), and CXCL12 (38.94 ± 5.07 pg vs. 83.59 ± 12.13 pg; p < 0.001). Conclusion Platelets in cancer patients cannot any longer be considered innocent bystanders. Instead, they may become activated upon their contact with intratumor/metastasis vascular walls and thereby secrete their quantitatively highly abnormal contents. While our data corroborate previous findings such as increased VEGF- and decreased tsp-1 content, we unexpectedly detected an additional decrease of CXCL12 and CXCL4. Whether megakaryocytes in solid tumor patients are responsible for their daughter cells' altered contents or whether platelets by means of their scavenger activity acquire the “malignant” phenotype remains to be established. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Thrombospondin-1 promotes haemostasis through modulation of cAMP signalling in blood platelets.

Blood ◽  
2020 ◽  
Author(s):  
Ahmed Aburima ◽  
Martin Berger ◽  
Benjamin EJ Spurgeon ◽  
Beth A Webb ◽  
Katie S Wraith ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Blood Platelets ◽  
Camp Signaling ◽  
Camp Accumulation ◽  
In Vivo Models ◽  
Downstream Signaling ◽  
Thrombospondin 1 ◽  
Increased Sensitivity

Thrombospondin-1 (TSP-1) is released by platelets upon activation and can promote platelet activation, but its role in haemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of haemostasis that promotes platelet activation by modulating inhibitory cAMP signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of haemostasis and thrombosis demonstrated that TSP-1 deficient mice had prolonged bleeding, defective thrombosis and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild type (WT), but not TSP-1-/- platelets, ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1-deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation and arrest under flow by PGI2. Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1-/- platelets. By contrast, incubation of TSP-1-/- platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1-/- platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1-/- mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This suggests that the release of TSP-1 regulates haemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.

STIM1 Deficiency Results In Impaired Platelet Procoagulant Activity and Protection From Arterial Thrombosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 485-485
Author(s):  
Firdos Ahmad ◽  
Lucia Stefanini ◽  
Timothy Daniel Ouellette ◽  
Teshell K Greene ◽  
Stefan Feske ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Critical Role ◽  
Phosphatidyl Serine ◽  
Flow Chamber ◽  
Procoagulant Activity ◽  
Static Conditions

Abstract Abstract 485 Platelet activation is a central event in thrombosis and hemostasis. We recently demonstrated that most aspects of platelet activation depend on synergistic signaling by two signaling modules: 1) Ca2+/CalDAG-GEFI/Rap1 and 2) PKC/P2Y12/Rap1. The intracellular Ca2+ concentration of platelets is regulated by Ca2+ release from the endoplasmic reticulum (ER) and store-operated calcium entry (SOCE) through the plasma membrane. Stromal interaction molecule 1 (STIM1) was recently identified as the ER Ca2+ sensor that couples Ca2+ store release to SOCE. In this study, we compared the activation response of platelets lacking STIM1−/− or CalDAG-GEFI−/−, both in vitro and in vivo. To specifically investigate Ca2+-dependent platelet activation, some of the experiments were performed in the presence of inhibitors to P2Y12. The murine Stim1 gene was deleted in the megakaryocyte/platelet lineage by breeding Stim flox/flox mice with PF4-Cre mice (STIM1fl/fl). STIM1fl/fl platelets showed markedly reduced SOCE in response to agonist stimulation. aIIbβ3 activation in STIM1fl/fl platelets was significantly reduced in the presence but not in the absence of the P2Y12 inhibitor, 2-MesAMP. In contrast, aIIbb3 activation was completely inhibited in 2-MesAMP-treated CalDAG-GEFI−/− platelets. Deficiency in STIM1, and to a lesser extent in CalDAG-GEFI, reduced phosphatidyl serine (PS) exposure in platelets stimulated under static conditions. PS exposure was completely abolished in both STIM1fl/fl and CalDAG-GEFI−/− platelets stimulated in the presence of 2-MesAMP. To test the ability of platelets to form thrombi under conditions of arterial shear stress, we performed flow chamber experiments with anticoagulated blood perfused over a collagen surface. Thrombus formation was abolished in CalDAG-GEFI−/− blood and WT blood treated with 2-MesAMP. In contrast, STIM1fl/fl platelets were indistinguishable from WT platelets in their ability to form thrombi. STIM1fl/fl platelets, however, were impaired in their ability to express PS when adhering to collagen under flow. Consistently, when subjected to a laser injury thrombosis model, STIM1fl/fl mice showed delayed and reduced fibrin generation, resulting in the formation of unstable thrombi. In conclusion, our studies indicate a critical role of STIM1 in SOCE and platelet procoagulant activity, but not in CalDAG-GEFI mediated activation of aIIbb3 integrin. Disclosures: No relevant conflicts of interest to declare.

Characteristics and outcomes of cancer patients ≥80 years treated with chemotherapy at a comprehensive cancer center

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8548-8548
Author(s):  
P. Jiang ◽  
M. Choi ◽  
D. Smith ◽  
L. Heilbrun ◽  
S. M. Gadgeel
Keyword(s):  
Cancer Patients ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
The United States ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Tumor Patients ◽  
Hematologic Cancer

8548 Background: The percentage of cancer patients ≥ 80 years old is expected to rise in the United States. However data are limited on use of chemotherapy in this group of patients. Methods: Retrospective identification of patients who received systemic chemotherapy at our cancer center between 1/1/2000 to 12/31/2004 was performed using the computer generated pharmacy data and medical records. Patients who had diagnosis of cancer and ≥ 80 years were included in the study; patients receiving only supportive care, hormonal therapy, or oral chemotherapy were excluded. The protocol for this study was approved by the Wayne State University IRB. Results: A total of 133 patients ≥ 80 years who received chemotherapy was analyzed. The median age was 83 and 31% of the patients were ≥ 85 years. There were more females (61%) than males (39%). The gender distribution was more even (47% v. 53%) after excluding gender specific tumors. The racial distribution was diverse- Whites 65 (49%); Blacks 41 (31%); Other 18 (13%); Unknown 9 (7%). 16% of the patients had hematologic malignancy and 84% had solid tumors. Gynecological cancers (32%) followed by aerodigestive cancers (26%) were the most common solid tumors. Solid tumor patients primarily had regional (48%) or distant (45%) disease. During the first regimen, 512 cycles of chemotherapy was delivered with a median of 3 cycles per patient (range 1–24 cycles); 40% of patients received only 2 cycles of chemotherapy. 64% of patients were able to receive chemotherapy without 2nd cycle delay. The distribution of single or multidrug regimens was fairly similar; Solid tumors 52% v. 48%; Hematologic cancers 43% v. 57%. Carboplatin and paclitaxel (22%) was the most common regimen among solid tumor patients. 26% of all patients received a second regimen. The 1 year survival rates among hematologic cancer and solid tumor patients were 65% and 48%, respectively. Stage of disease was the only statistically significant factor predicting survival. Conclusions: In this diverse group of cancer patients ≥ 80 years old and selected for chemotherapy, the treatment was feasible. The survival outcomes in this elderly population were comparable to those of a younger patient population suggesting that the treatment is beneficial. No significant financial relationships to disclose.

Species distribution and antimicrobial susceptibility profile of gram-negative bacteria in hospitalized cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20730-e20730
Author(s):  
H. M. Ashour ◽  
A. El-Sharif
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Cancer Patients ◽  
Solid Tumor ◽  
Klebsiella Pneumonia ◽  
Gram Negative Bacteria ◽  
Isolation And Identification ◽  
Tumor Patients ◽  
Acinetobacter Species ◽  
Gram Negative

e20730 Background: Nosocomial infections pose significant threats to hospitalized patients, especially the immunocompromised ones, such as cancer patients. Methods: This study examined the microbial spectrum of gram-negative bacteria in various infection sites in patients with leukemia and solid tumors. The antimicrobial resistance patterns of the isolated bacteria were studied. Results: The most frequently isolated gram-negative bacteria were Klebsiella pneumonia (31.2%) followed by Escherichia coli (22.2%). We report the first-time isolation and identification of a number of less-frequent gram negative bacteria (Chromobacterium violacum, Burkholderia cepacia, Kluyvera ascorbata, Stenotrophomonas maltophilia, Yersinia pseudotuberculosis, and Salmonella arizona). Most of the gram-negative isolates from RTI, GITI, UTI, and BSI were obtained from leukemic patients. All gram-negative isolates from SI were obtained from solid-tumor patients. In both leukemic and solid-tumor patients, gram-negative bacteria causing UTI were mainly Escherichia coli and Klebsiella pneumoniae, while gram-negative bacteria causing RTI were mainly Klebsiella pneumoniae. Escherichia coli was the main gram-negative pathogen causing BSI in solid-tumor patients and GITI in leukemic patients. Isolates of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, and Acinetobacter species were resistant to most antibiotics tested. There was significant imipenem-resistance in Acinetobacter (40.9%), Pseudomonas (40%), and Enterobacter (22.2%) species, and noticeable imipinem-resistance in Klebsiella (13.9%) and Escherichia coli (8%). Conclusions: This is the first study to report the evolution of imipenem-resistant gram-negative strains in Egypt. Mortality rates were higher in cancer patients with nosocomial Pseudomonas infections than any other bacterial infections. Policies restricting antibiotic consumption should be implemented to avoid the evolution of newer generations of antibiotic resistant-pathogens. No significant financial relationships to disclose.

Oncologist- versus hospitalist-led service: Differences in hospital utilization for solid tumor patients.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 53-53
Author(s):  
Lesley Wu ◽  
Minira Aslanova ◽  
Haley Hines Theroux ◽  
Hsin-hui Huang ◽  
Cardinale B. Smith
Keyword(s):  
Palliative Care ◽  
Cancer Patients ◽  
Solid Tumor ◽  
Quality Care ◽  
Hospital Utilization ◽  
Bivariate Analysis ◽  
Hospital Inpatient ◽  
Cancer Type ◽  
Inpatient Mortality ◽  
Tumor Patients

53 Background: Hospitalists have been practicing alongside oncologists to provide high quality care for hospitalized cancer patients. We examined the differences in hospital utilization and outcomes among solid tumor patients admitted to oncologist-led teams (OT) versus hospitalist-led teams (HT). Methods: We performed a retrospective cohort study of patients with solid tumors admitted to the OT or HT at Mount Sinai Hospital from July to December 2019. We excluded patients less than 18 years of age, primary hematologic malignancies, or admission to intensive care or surgical units. We used the Activity Measure for Post Acute Care (AMPAC) and Charlson Comorbidity Index as a measure of functional ability and illness severity, respectively. We performed bivariate and multivariate analyses comparing differences in length of stay, ICU transfers, palliative care consults, healthcare proxy (HCP) decision, new DNR decision, readmission within 30 days and inpatient mortality by type of admitting service (OT vs HT). Results: A total of 544 patients were identified; 61% (334) admitted to HT. There were significant differences according to race and cancer type (p= 0.001 for both). HT patients had more functional impairment (p<0.0001) and poorer prognosis (p=0.0002). In bivariate analysis, HT had significantly more ICU transfers (OT, 2% vs HT, 8%; p=0.008), new DNR decisions (OT, 7% vs HT, 16%; p=0.002), and inpatient mortality (OT, 4% vs HT, 9%; p=0.02) while OT had significantly more palliative care consults (OT, 45% vs HT, 20%; p<0.0001). Multivariate analysis (Table) demonstrates HT had significantly more new DNR decisions (odds ratio [OR]: 0.46, 95% confidence interval [CI]: 0.23-0.93) and OT had significantly more palliative care consults (OR: 4.01, 95% CI: 2.51-6.43). Conclusions: At our academic hospital, inpatient cancer care led by hospitalists is comparable to that of oncologists despite HT caring for more severely ill oncology patients. From a value perspective, hospitalists facilitating care for hospitalized cancer patients will allow oncologists to maximize ambulatory time and focus on active cancer treatment. [Table: see text]

scholarly journals Versican Proteolytic Fragments (Matrikines) Regulate the Intratumoral Dendritic Cell Milieu In Vivo: Implications for in Situ Tumor Vaccination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1210-1210 ◽  
Author(s):  
Athanasios Papadas ◽  
Evan Flietner ◽  
Zachary Morrow ◽  
Joshua Wiesner ◽  
Alexander Cicala ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Tumor Microenvironment ◽  
Solid Tumor ◽  
Conflicts Of Interest ◽  
P Value ◽  
Tumor Site ◽  
Tumor Models ◽  
Differentiation Potential

Regulated proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) through the actions of ADAMTS-proteases, is associated with enhanced CD8+ infiltration in both hematopoietic and solid tumors. However, it is unclear whether the enhanced CD8+ infiltration results from proteolysis-mediated depletion of precursor VCAN at the tumor site or from generation of bioactive proteolytic fragments ("matrikines") (e.g., the 441-aa N-terminal fragment of V1-VCAN isoform, versikine). We have previously shown that versikine promotes Batf3-dendritic cell (DC) generation from FLT3L-mobilized bone marrow (BM) progenitors in vitro. However, the effects of versikine in DC homeostasis in the tumor microenvironment in vivo are unknown. To investigate the effects of versikine in DC homeostasis in vivo, we utilized the first Ras-driven myeloma (MM) model (VQ model- Rajagopalan et al., Blood 132:1006, 2018) as well as transplantable solid tumor models in both C57BL/6J (LLC lung carcinoma) and Balb/c (4T1 mammary carcinoma) backgrounds. Tumor cells were stably engineered to secrete HA-tagged versikine vs. empty-vector (EV) controls. EV-VQ or versikine-VQ myeloma cells were implanted intracardiacally into C57BL/6J syngeneic recipients and mice were monitored until they developed myeloma-related end-organ damage (hindlimb paralysis). Both groups of mice were paralyzed at similar rates. Intratumoral conventional DCs (CD138-CD45+, CD11chi,MHC IIhiLy6C-, CD64-) clustered into two populations: cDC1 (Batf3-DC: CD24hi,CD11blo), a subset with crucial activity in cross-priming anti-tumor CD8+ T cells, and cDC2 (CD24lo, CD11bhi). Versikine enhanced intratumoral Batf3-DC frequency/infiltration, while cDC2 levels were diminished in versikine-VQ BM (Figure 1A)(Batf3-DC: 48% in EV-VQ vs. 72% in versikine-VQ, p-value= 0.0246; cDC2: 52% in EV-VQ vs. 28% in versikine-VQ, p=0.0312). Monocytic-derived DC (Mo-DC: CD11chi, MHC IIhi, Ly6C+, CD64+) frequency remained unchanged. Versikine's effects were replicated in 2 solid tumor models. Versikine-expressing tumors were characterized by significantly enhanced Batf3-DC infiltration (Fig. 1A, p-value= 0.0079 for 4T1 model and <0.0001 for LLC model), whereas cDC2 numbers were diminished (p-value: 0.0079 and <0.0001 respectively). Adoptive transfer of CD45.2+ pre-DC (SIRPaint, FLIT3+, CD11c+, MHC II-, Celltrace+) in LLC-EV and LLC-versikine tumors in CD45.1+ recipients did not show any differences in 3-day differentiation potential of DC precursors, implicating other mechanisms to explain the steady-state imbalance in DC subset frequencies. To examine whether versikine's effects on the intratumoral DC milieu in vivo could be therapeutically harnessed, we compared responses to STING agonist therapy between versikine-expressing and EV tumors. LLC-EV-OVA and LLC-versikine-OVA (ovalbumin, a model antigen) -expressing tumors received therapeutic intratumoral injections of DMXAA, a murine STING agonist. Analysis of splenocytes 5 days later showed a significant increase in the frequency of OVA antigen-specific, CD8+ (MHCI:SIINFEKL tetramer+) splenocytes in LLC-versikine-bearing animals (Figure 1B). Interestingly, there was a marked increase in total central memory T splenocytes (TCM) (CD62LhiCD44hi) harvested from LLC-versikine tumor-bearing mice. We conclude that versikine influences the DC milieu in the tumor bed with promotion of intratumoral cross-presenting Batf3-DC and depletion of the cDC2 subset. Our findings highlight an unappreciated facet of immune regulation of the tumor microenvironment through matrix proteolytic fragments ("matrikines"). Whereas detection of native VCAN proteolysis on myeloma biopsies (see abstract by Dhakal et al.in this meeting) portends adverse outcomes likely due to the tolerogenic effects of accumulated precursor VCAN at the tumor site, therapeutic use of the isolated, purified fragments may promote tumor innate sensing and effector priming. VCAN-matrikines, through their effects on intratumoral Batf3-DC and antigen-specific CD8+ T cell infiltration, may potentiate in situ vaccination strategies across diverse hematopoietic and solid tumor types. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals 293. Lung Cancer and Hematologic Malignancy ( HM) Patients Are Associated with the Highest Risk of Progressing to Severe Disease and Mortality in Cancer Patients with COVID-19

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S254-S254
Author(s):  
Anne-Marie Chaftari ◽  
Alexandre Malek ◽  
Hiba Dagher ◽  
Ying Jiang ◽  
Arnaud Bayle ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mortality Rate ◽  
Cancer Patients ◽  
Solid Tumor ◽  
Hematologic Malignancy ◽  
Severe Disease ◽  
Panel Member ◽  
Severe Illness ◽  
Review Panel ◽  
Tumor Patients

Abstract Background Several studies have shown that underlying cancer is a risk factor for progression of COVID-19 to severe illness and fatal outcome but there is very little data that specifies which underlying cancer puts this patient population at the highest risk. Methods We retrospectively collected de-identified data on 1115 cancer patients diagnosed with COVID-19 between January and November 2020, at 12 centers in Asia, Australia, Europe, North America, and South America. Patient characteristics including age, type of malignancy (hematologic malignancy [HM], lung cancer, and non-lung cancer were determined in association with severe illness as well as all-cause mortality within 30 days after COVID-19 diagnosis. Results By multivariable logistic regression analysis, independent risk factors for 30-day mortality in cancer patients included age &gt; 65 (OR 6.64; 95% CI 3.351to 12.55; p&lt; 0.0001), ALC &lt; 0.5 K/microliter (OR 2.10; 95% CI 1.16 to 3.79; p=0.014), and anemia at &lt; 10g/dl (OR 2.41; 95% CI 1.30 to 4.44; p=0.005). Among cancer patients, the 30-day mortality rate was significantly higher in patients with lung cancer than in patients with non-lung cancer solid tumors, including those with lung metastases (22% vs 9%; p=0.001). Patients with HM tended to have higher 30-day mortality than patients with non-lung cancer solid tumors (13% vs 9% p=0.07) and tended to have a lower mortality rate than patients with lung cancer (p=0.07). Furthermore, HM patients were more likely to be lymphopenic and anemic at diagnosis as well as progress to LRTI and be placed on ventilatory support compared to non-lung cancer solid tumor patients ( p= or &lt; 0.01). In addition, lung cancer and HM patients were more likely to develop hypoxia and require hospital admission than non-lung cancer solid tumor patients ( p=0.01). Conclusion Lung cancer and HM patients are associated with the highest risk of progressing to severe disease and mortality in cancer patients with COVID-19. Hence, cancer patient population should be given the highest priority as far as prevention [vaccination with boosters if needed] as well as preemptive early therapy with monoclonal antibodies right after the onset of COVID-19. Disclosures Monica Slavin, MBBS,MD, F2G (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Pfizer (Advisor or Review Panel member)

Effect of Chemotherapy Treatment on Fetal-Maternal Microchimerism in Parous Cancer Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5134-5134
Author(s):  
Gary L. Gilmore ◽  
Melissa M. Holm ◽  
Yuliya Anikanova ◽  
Bushra Haq ◽  
Sri Lakshmi Jasthy ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Solid Tumor ◽  
Hematologic Malignancy ◽  
Post Partum ◽  
Hematologic Malignancies ◽  
Tumor Patients ◽  
Specific Sequence ◽  
Benign Condition ◽  
The Difference ◽  
Primer Sets

Abstract Fetal-maternal microchimerism [MC] is a benign condition arising from cross-trafficking of circulating cells between the fetus and the mother during gestation. It is known that MC persists for decades post-partum. The reported incidence of MC is 33% in normal parous women, but the MC status of cancer patients has not been examined. We have completed our study of 200 parous cancer patients, using a sensitive two-round PCR technique with nested primer sets specific for the Y-chromosome specific sequence, DSY14, to detect male DNA in blood samples from female patients. Exhaustive analysis of samples from parous cancer patients gave a frequency of 34% MC+ [68 of 200], which is significantly lower than the 57% MC+ [114 of 200] we found in normal parous women [p&lt;.0001]. We reported an apparent dichotomy based on diagnosis, in that patients with hematologic malignancies had a greater frequency of MC than solid tumor patients [46% vs 29%; p&lt;.0001]. Both groups received similar numbers of chemotherapy cycles [3.4 cycles for solid tumor patients; 3.2 for hem/onc patients], suggesting this difference was not due to less intensive treatment. When we separated the untreated patients from each population, we found that only 25% [3 of 12] untreated patients with hematologic malignancies were MC, whereas 32% of untreated solid tumor patients were MC+ [12 of 38; p=.66, ns]. Therapy appeared to increase the frequency of MC in hematologic patients to 52% [25 of 48; p=.09, ns], but MC was essentially unaffected in solid tumor patients [27%, 28 of 104; p = .18, ns]. The difference between treated solid tumor patients and those with hematologic malignancies was significant [p=.0001]. Thus, one side effect of chemotherapy may be to increase MC in hematologic malignancy, but in solid tumor patients, MC is not affected. The reason for the increased MC in treated hematologic patients in unclear, but we speculate the reduced frequency in untreated patients is due to dilution by the malignant clone, and that chemotherapy restores the normal balance of blood cells in these patients. The reason for reduced MC in solid tumor patients is also not obvious, as DNA yields are roughly equivalent between the two groups of cancer patients. Further analysis of the data is underway to see if an underlying cause can be determined.

Biphasic Roles for the Soluble Guanylyl Cyclase (sGC) In Platelet Activation In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 486-486
Author(s):  
Guoying Zhang ◽  
Binggang Xiang ◽  
Radek C. Skoda ◽  
Susan S. Smyth ◽  
Xiaoping Du ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Guanylyl Cyclase ◽  
Conflicts Of Interest ◽  
Soluble Guanylyl Cyclase ◽  
Wild Type ◽  
No Donor ◽  
Cgmp Production ◽  
Deficient Mice

Abstract Abstract 486 The role of intracellular secondary messenger cGMP in platelet activation has been controversial, with both stimulatory and inhibitory roles reported. The platelet cGMP is believed to be predominantly synthesized by soluble guanylyl cyclase (sGC), which is activated by nitric oxide (NO). To specifically determine the role of sGC-dependent cGMP synthesis in platelet function and in vivo thrombosis and hemostasis, we produced mice harboring a “floxed” sGC beta1 allele. In the “floxed” sGC beta1 mice (sGC beta1fl/fl), the exons 7 and 8 of sGC beta1 gene and an inserted Neo cassette were flanked with three LoxP sites. Platelet-specific deletion of sGC beta1fl/fl allele was accomplished through breeding of the sGC beta1fl/fl mice with pf4-Cre recombinase transgenic mice. Immunoblotting showed the complete absence of this protein in sGC beta1fl/fl/Cre platelets. Mice lacking sGC beta1 in platelets appeared to develop normally and had normal blood counts, including platelets. Blood pressure of platelet-specific sGC deficient mice was comparable to that of wild-type littermates. Inactivating the sGC beta1 gene in platelets abolished cGMP production induced by either NO donors or platelet agonists that are known to activate endogenous NO synthesis, confirming that both the platelet agonist-induced and NO donor-induced platelet cGMP production are predominantly mediated by sGC. Platelets lacking sGC exhibit a marked defect in aggregation and secretion in response to low doses of platelet agonists, collagen and thrombin. Importantly, tail-bleeding times were significantly prolonged in the platelet-specific sGC deficient mice compared with the wild-type littermates. In a FeCl3-induced carotid artery thrombosis model, time to occlusive thrombosis was prolonged in the platelet-specific sGC deficient mice, compared to wild type littermates. Thus, the agonist-stimulated sGC activation is important in promoting platelet granule secretion and aggregation. On the other hand, NO donor SNP-induced inhibition of platelet activation was abolished in sGC-deficient platelets. However, at high concentrations (>100μM), SNP inhibited platelet activation in both wild type and sGC deficient mice, indicating that both cGMP-dependent and -independent mechanisms are involved in NO donor-induced inhibition of platelet activation. Together, our data demonstrate that sGC contributes to both agonist-induced platelet activation and NO donor-induced platelet inhibition. Disclosures: No relevant conflicts of interest to declare.

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